JPS6037118B2 - penicillanic acid derivatives - Google Patents

Description

[Detailed description of the invention] The present invention relates to benicilane acid converters.

The compound of the present invention is a novel compound not yet known in the literature, and has the general formula: [where RI represents a hydrogen atom, a lower alkanoyl group, or a lower alkasulfonyl group, and R2 represents a hydrogen atom or a hydroxyl group, respectively.

] Benicillanic acid derivatives and salts thereof.
The compounds of the present invention have excellent antibacterial activity against Gram-positive and Gram-negative bacteria and are useful as antibacterial agents.

The compounds of the present invention exhibit remarkable antibacterial activity, particularly against Pseudomonas aeruginosa and Bacillus luteinus. In the above general formula {1, a lower alkanoyl group represented by RI and a straight mirror or branched alkanoyl group having 1 to 4 carbon atoms can be mentioned, and specific examples include formyl, acetyl, propionyl, and butyryl. ,
An example is an isobutyryl group.

Examples of the lower alkasulfonyl group represented by RI include groups in which the above-mentioned lower alkyl group and sulfonyl group are bonded, and specific examples include methanesulfonyl, ethanesulfonyl, pro/gunsulfonyl, inpropanesulfonyl, and butanesulfonyl. Examples include sulfonyl and rt-butanesulfonyl groups. Representative compounds of the present invention are listed below.

o6-{2-[8-(1-piverazinyl)-6,7-dihydro-1-oxo IH,QH-penzo[ij]quinolidine-2-ruboxamide]-2-phenylacetamide}-3,3-dimethyl 2, 0] hebutane-2-carboxylic acid o6-{2-[8-(1-piverazinyl)-6,
7-dihydro 1-oxo-IH,9H-penzo[ij
[Quinolidine-2-carboxamide]-2-(4-hydroxy)phenylacetamide}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0
] Hebutane-2-carboxylic acid.

6-{2-[8-(4-acetyl-1-piverazinyl)
-6,7-dihydro-1-oxo IH,SH-penzo[ij]quinolidine-2-carboxamide]-2-phenylacetamide}-3,3-dimethyl-7-oxo-
4-Cheer 1-Azabicyclo[3.2,0]hebutane-
2-carboxylic acid o6-{2-[8-(4-formyl-1
-piverazinyl)-6,7-dihydro-1-oxo-I
H, 9-day-benzo[jj]quinolidine-2-carboxamide]-2-(4-hydro.

xy)phenylacetamide}63,3-dimethyl-7-oxo-4-thia-1-azapicyclo[3,2,0
] Hebutane-2-carboxylic acid o6-{2-[8-(4-
butyryl-1-piverazinyl)-6,7-dihydro-1
-oxo-IH,9H-penzo[ij]quinolidine-2
-carboxamide]-2-phenylacetamide}-3
,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0]butane-2-carboxylic acid o6-{
2-[8-(1-methanesulfonyl-1-1-piverazinyl)
-6,7-dihydro1-oxo IH,9H-penzo[ij]quinolidine-2-carboxamide]12-phenylacetamide}-3,3-dimethyl-7-oxo4-thia1-azabicyclo[3,2 ,0]hebutane-
2-carboxylic acid o6-{2-[8-(4-ethanesulfonyl-1-piverazinyl)-6,7-dihydro-1-oxo IH,9H-penzo[ij]quinolidine-2-hydro-ruboxamide]-21(4-hydroxy ) phenylacetamide}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0]hebutane-2-carboxylic acid o6-{2-[8-1 (4-butanesulfonyl-1
-piverazinyl)-6,7-dihydro-1-oxo I
H,9H-penzo[ij]quinolidine-2-carboxamide]-2-phenylacetamide}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2
. can be done.

[In the formula, RI is the same as above.

] Penzo[ij]quinolidine-2 represented by the general formula ■
The -carboxylic acid derivative is a new compound, and can be produced, for example, as shown in Reaction Scheme 1 below.

Reaction Scheme-1 [In the formula, R3 represents a halogen atom, a lower alkanesulfonyloxy group, or a p-toluenesulfonyl group.

RI is the same as above. ] That is, the compound of the general formula ■ is the compound of the general formula [
It is produced by reacting the compound of formula '3} and the compound of general formula '4}.

Among the compounds of the general formula glue, the compound in which R3 represents a halogen atom is a known compound or can be easily produced according to a known method [Japanese Patent Publication No. 51-6156, USP
No. 4014877]. In the compound of general formula '3}, R3 is a lower alkanesulfonyloxy group or p
Compounds exhibiting -toluenesulfonyloxy group (general formula (
Powder)) is a new compound, and is produced, for example, by the method shown in Reaction Scheme-2 below. The lower alkanesulfonyloxy group represented by R3 includes methanesulfonyloxy, ethanesulfonyloxy, pro/gunsulfonyloxy, isopropanesulfonyloxy, butanesulfonyloxy, and rt-butanesulfonyloxy groups. Reaction Scheme-2 [In the formula, R4 represents a lower alkanesulfonyl group or p-toluenesulfonyl group, R5 represents a lower alkyl group, and x represents a halogen atom.

] That is, the compound of general formula (3) is obtained by reacting the compound of general formula (2) with the compound of general formula (2), and then the compound of general formula '71
The compound of the general formula {8) obtained is then reacted with the compound of the general formula {9), and the compound of the general formula OQ obtained is further reduced, and then the compound of the general formula (1) obtained is reduced.
It is produced by hydrolyzing the compound of 1).

In the reaction between the compound of general formula {51 and the compound of general formula good.

The reaction is usually carried out in an inert solvent in the presence of an acid scavenger. Specific examples of deoxidizing agents include alkali metal oxides such as sodium hydroxide and potassium hydroxide, sodium carbonate,
Examples include inorganic carbonate compounds such as potassium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate, and tertiary amines such as pyridine, quinoline, and triethylamine. Such a deoxidizing agent is usually used in an amount equal to or more than the same mole relative to the compound of general formula {5},
It is preferable to use equimolar to twice the molar amount. Inert solvents that can be used include lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane, tetrahydrofuran, and diglyme, aromatic hydrocarbons such as benzene and toluene, dimethyl sulfoxide, dimethylformamide, and hexane. Examples include methylphosphoric triamide and pyridine. The reaction is usually 0 to 10
It is carried out at 0°C, preferably around room temperature, and usually 0.5~
The reaction is completed in about 6 hours. A compound of general formula '71 is thus produced. A catalytic reduction method, a reduction method using a hydrogenating agent, etc. can be applied to the reduction of the compound of general formula '7}.

Reduction with a hydrogenating agent is preferred. Examples of the hydrogenating agent include hydrogenating agents prepared by appropriately combining sodium borohydride or lithium aluminum hydroxide with lower fatty acids such as acetic acid, trifluoroacetic acid, and propionic acid. The amounts of sodium borohydride or lithium aluminum hydride and lower fatty acids to be used are preferably equimolar to excess, preferably 3 to 5 times the molar amount of the compound of general formula {7]. The reduction reaction with a hydrogenating agent is carried out in an inert solvent. Specific examples of the inert solvent used include ethers such as dioxane, tetrahydrofuran and diglyme, aromatic hydrocarbons such as benzene and toluene, and lower fatty acids such as acetic acid, trifluoroacetic acid and propionic acid. The reaction is usually carried out at room temperature to 100°C, preferably 50 to 100°C, and is usually completed in about 1 to 6 hours. In this way, a compound of general formula (1) can be obtained. The reaction between the compound of general formula (1) and the compound of general formula '91 is carried out without a solvent or in a solvent such as methanol, isopropanol, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid amide, etc., preferably without a solvent.

The proportion of compound [9} to be used in relation to compound (■) should normally be at least equimolar, preferably equimolar in the reaction without a solvent, and preferably 1.1 to 1.5 tomolar in the reaction in a solvent. It is better to do so. The reaction temperature is usually from room temperature to about 150°C, preferably from 100 to 130 q○, the reaction is usually completed in 0.5 to 6 hours, and the general formula represented by the general formula can be easily obtained. The reflux reaction of the compound '10 thus obtained can be carried out according to various conventionally known cyclization reactions.

For example, heating method, phosphorus oxychloride, phosphorus pentachloride,
Examples include cyclization methods using acidic substances such as phosphorus trichloride, thionyl chloride, concentrated sulfuric acid, and polyphosphoric acid. When employing a cyclization method by heating, a solvent such as high-boiling hydrocarbons and high-boiling ethers such as tetralin, diphenyl ether, diethylene glycol dimethyl ether, etc. is used,
Usually 100-250℃, preferably 150-200qo
heating conditions can be adopted. In addition, when an oxidation method using an acidic substance is employed, it is used in an equimolar amount to a large excess amount relative to the compound side, preferably at a volume of 10 to 2, usually 100 to 150.
oo for about 0.5 to 6 hours. In this way, a compound of general formula (11) is produced. The hydrolysis reaction of compound (11) obtained by the above cyclization reaction can be carried out using a basic compound such as sodium hydroxide, potassium hydroxide, or barium hydroxide, hydrochloric acid such as sulfuric acid, hydrochloric acid, or nitric acid, or acetic acid. , in the presence of conventional catalysts such as organic acids such as aromatic sulfonic acids.

The reaction is generally carried out in conventional solvents such as water, methanol, ethanol, isopro/benol, acetone, methyl ethyl ketone, dioxane, ethylene glycol, acetic acid and the like. The reaction temperature is normal temperature to 200 qo, preferably 50 to 150°C. In this way, the compound of general formula ($) is easily obtained. The compound of general formula (4) is a known compound or can be easily produced according to a known method.

In the reaction between the compound of the general formula glue and the compound of the general formula '4-, the ratio of the two to be used is not particularly limited and may be appropriately selected within a wide range, but usually the latter is used in equimolar amounts to the former. It is preferable to use an amount equal to or more than the amount, preferably an equimolar to 5 times the molar amount.

The reaction is carried out in an inert solvent. Specifically, such solvents include water, lower alcohols such as methanol, ethanol, and isopropanol, benzene, toluene,
Aromatic hydrocarbons such as xylene, tetrahydrofuran,
Examples include ethers such as dioxazo and diglyme, dimethyl sulfoxide, dimethyl formamide, and hexamethyl phosphoric triamide. Among these, dimethylsulfoxide, dimethylformamide and hexamethylphosphoric triamide are preferred. The reaction is usually carried out at 1 to 2 atmospheres (
Preferably under a pressure of 1 to 1 atmospheric pressure, 100 to 2500
The reaction is generally completed in about 5 to 2 field hours. In this way, a compound represented by the general formula [21] is synthesized. Compound (2
There are various methods for producing the benicilane acid converter of the present invention using .

1. A method of reacting compound [2) or its carboxyl group active compound with known ampicillins or its amino group active compound.

2. A method of reacting compound (1) or its carboxyl group active compound with phenylglycines or its amino group active compound, and then reacting it with 6-aminobenicillanic acid or its amino group active compound.

Each of the above methods can be easily carried out according to known amide bond forming reactions; for example, method 1 above can be carried out by the following various methods.

Mixed acid anhydride method A method in which a compound (■) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, and ampicillins are reacted with this.

[ol Active ester method A method in which the compound (1) is converted into an active ester such as para-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and ampicillin is reacted with the active ester.

1. Carbodiimide method A method in which compound t2} and ampicillin are subjected to dehydration condensation in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or luponyldiimidazole.

9 Other methods and compounds in which compound (1) is converted into an anhydride form using a dehydrating agent such as acetic anhydride, or into an acid halide form using a halogenating agent, and then reacted with ampicillins.
A method in which ampicillin is reacted with an ester of 1 and a lower alcohol under high temperature and pressure.

The mixed acid anhydride method, which is a particularly preferred method among the above methods, is carried out more specifically as shown in the following reaction scheme-3.

Reaction Scheme-3 [In the formula, R6 is a lower alkyl group, X is a halogen atom,
M represents a hydrogen atom or an alkali metal atom, respectively.

RI and R2 are the same as above. ] In the above reaction scheme-3, the reaction between the compound (1) and the alkylhalocarboxylic acid represented by the general formula (12) may be carried out according to the usual Schotten-Baumann reaction, resulting in the reaction of the general formula (13).
The carboxyl-active compound of compound t2} represented by formula (14) can be subsequently reacted with ampicillins represented by general formula (14) without being isolated.

The Schotten-Baumann reaction between compound (1) and compound (12) above can be carried out without a solvent in the presence of a basic compound, but preferably chloroform, dichloromethane, dichloroethane, acetonitrile, DMF, DMS.
○, carried out in the presence of a basic compound in a suitable solvent such as hexamethylphosphate amide. Basic compounds include amines such as triethylamine, trimethylamine, pyridine, dimethylaniline, and N-methylmorpholine, and inorganic or organic compounds such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium acetate, and sodium propionate. Examples include metal salts. Further, examples of the alkylhalocarboxylic acid represented by the general formula (12) include methyl chloroformate, methyl bromoformate,
Ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, etc. can be used. Compound of the equivalent compound (12)'
The ratio of use to the skin can be determined arbitrarily as long as it is usually equimolar or more, but if a solvent is used, it is preferably 1.1 to 1.
．． It is best to set it to about 100 ml. The reaction temperature is about 120°C to 30°C, preferably 0°C to room temperature, and the reaction is completed in about 0.5 to 3 hours. The reaction between the compound represented by the general formula (13) obtained by the above reaction and the ampicillins represented by the general formula (14) proceeds advantageously in the above reaction solvent or in a mixed solvent of this and water. The proportion of ampicillin to be used is usually equal to or more than equimolar, preferably 1 to 1.5 tomolar relative to compound (13). The reaction temperature is usually room temperature to about 100q0, preferably room temperature.
The reaction is generally complete within 2 to 1 feeding period. Further, the above method 2 for obtaining the benicilane acid converter of the present invention is carried out in more detail as shown in the following reaction scheme 14.

Reaction formula-4 [In the formula, R1, Rq and M are the same as above.

] That is, the compound {2} or its carboxyl group activated compound is reacted with a phenylglycine represented by the general formula (15) to obtain a compound represented by the general formula (16),
Then, -6 represented by formula (17) is added to the compound (16).
The penicillin derivative '1' of the present invention can be obtained by reacting aminobenicillanic acid or a salt thereof.

Each reaction in the above is, for example, the reaction scheme-3 described above.
This can be easily carried out according to the known amide bond forming reaction as shown in FIG.

The benicillanic acid derivative represented by the general formula '11 of the present invention thus obtained can be made into a pharmacologically acceptable acid addition salt thereof, and the present invention also includes this acid addition salt.

The acid used to form the acid addition salt may be any pharmacologically acceptable organic or inorganic acid, including, for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, and acetic acid; Examples include organic acids such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, masoderic acid, ethane sulfonic acid, and p-tosylic acid. Further, the compound represented by the general formula {1} of the present invention can be treated with a pharmaceutically acceptable basic compound to form a carboxylate salt.

Examples of the basic compounds that can be used include inorganic basic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, and sodium hydrogen carbonate, as well as morpholine, piperazine, pyridine, piperidine, ethylamine, dimethylamine, triethylamine, Examples include organic basic compounds such as aniline. The thus obtained benicillanic acid derivative represented by the general formula {1) of the present invention and its salt can be easily isolated and purified by conventional separation means after the above-mentioned reaction steps are completed.

Examples of separation means include solvent extraction, dilution, recrystallization, column chromatography, and preparative thin layer chromatography. The compounds of the present invention can take the form of optical isomers, and the present invention also includes these optical isomers.

When the benicillanic acid converter and its salt represented by the general formula '1} of the present invention thus obtained are used as an antibacterial agent, they are usually put into the form of a pharmaceutical composition together with a pharmaceutical carrier.

The rods include fillers, extenders, binders, wetting agents, disintegrants,
Examples include diluents such as surfactants and lacquers, and excipients. Various dosage unit forms of antibacterial agents can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, solutions, suspensions, emulsions, parent granules, capsules, and suppositories. , injections (solutions, suspensions, etc.), ointments, etc.

When forming tablets, a wide variety of substances conventionally known in this field can be used, such as lactose, sucrose,
Sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicon, water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose , potassium phosphate, binders such as polyvinylpyrrolidone, dried starch,
Disintegrants such as sodium alginate, agar powder, laminaria powder, sodium bicarbonate, calcium carbonate, Win, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc. , quaternary ammonium,
Absorption enhancers such as sodium lauryl sulfate, glycerin,
Insulating agents such as starch, starch, lactose, kaolin, bentonite, etc. Adsorbents such as silicic acid, purified talc,
Examples include thickening agents such as stearate, boric acid powder, macrogol, and solid polyethylene glycol. When molding into pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, hard kaolin, talc, gum arabic, etc. powder, tragacanth powder, gelatin,
Examples include binders such as ethanol, and disintegrants such as laminaria and agar. Furthermore, tablets may be coated with conventional coatings as required, such as bran-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets,
They can be film-coated tablets, double tablets, or multilayer tablets. When forming into a suppository, a wide range of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When prepared as injectables, solutions and suspensions are preferably sterile and isotonic with blood; when they are formed into solutions, emulsions and suspensions, diluents known in the art are used. All commonly used alcohols can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene solpit, solpitan ester, etc. . In this case, the antibacterial agent may contain a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution, and the antibacterial agent may also contain conventional solubilizing agents, buffers, disease-neutralizing agents, preservatives, etc. Furthermore, coloring agents, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals may be included in the therapeutic agent, if necessary. base, cream
When molding into the form of a film or gel, a wide variety of diluents conventionally known in this field can be used, such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, and the like. The amount of the compound of the present invention to be included in the antibacterial agent is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 7% by weight based on the total composition.

Furthermore, there are no particular restrictions on the use of the above-mentioned antibacterial agents, and they can be administered in a manner appropriate for various forms. For example, in the case of tablets, pills, solutions, suspensions, emulsions, jaw granules, and capsules, it is administered orally, and in the case of injections, it is administered intravenously either alone or mixed with normal replacement fluids such as glucose and amino acids. Administered internally,
Furthermore, if necessary, it can be administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally; in the case of a suppository, it can be administered rectally; and in the case of an ointment, it can be applied. The dosage of the compound of the present invention as an antibacterial agent is appropriately selected depending on the purpose of use, symptoms, etc.
Usually, the compound of the present invention is administered 9 to 5 times per day/bdy.
A pharmaceutical composition containing approximately y of seawater may be administered in 3 to 4 doses.

<Antibacterial action> The compound of the present invention, 6-{2-[8-(4-acetyl-1-piverazinyl)-6,7-dihydro-1-oxy-IH,OH-penzo[ij]quinolidine-2-ruboxamide] -2-phenylacetamide}-3,3-dimethyl-7-oxy-4-thia-1-azabicyclo[3
,2,0]hebutane-2-carboxylic acid (compound A) and 6-{2-[8-(1-piverazinyl)-6,7-dihydro-1-oxy-IH,9-day-benzo[ij]quinolidine-2-carboxamide] 121-phenylacetamide}-3,3-dimethyl-7-oxy-4-thia-1-
The antibacterial activity of azabicyclo[3,2,0]hebutane-2-carboxylic acid (compound B) against various bacteria was determined by the agar dilution plate method.

The minimum growth-inhibiting concentrations obtained are shown in Table 1 below. In addition, each type of bacteria is 1 x 1 bacteria/person (0.D.660 skin Buddha, 0.13
~0.14) and 1×1 bacterial count/prepared on paper. 1st
Reference examples, examples, and formulation examples are listed below the table.

Reference example 1 potassium hydroxide 3.8 parts methanol 100 parts
5-hydroxy-3,4-dihydrocarbostyryl was added to the solution dissolved in water for 30 minutes at room temperature, and then the methanol was removed under reduced pressure. Benzene is added to the residue, and after crystallization, the benzene is removed. The residue was suspended in 50 parts of dimethylformamide, and 10.6 parts of ice-cooled methanesulfonyl chloride was added dropwise. After the addition, 3.5 hours of methanesulfonyl chloride was further added dropwise, and the mixture was incubated at room temperature for 4 hours. After the reaction was completed, the solvent was removed under reduced pressure.
The residual solution was isolated and purified by silica gel column chromatography (silica gel; Wako C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), eluent: chloroform), and then recrystallized from aqueous ethanol to obtain colorless columnar crystals of 5-methanesulfonyloxy. -3,
4-dihydrocarbostyryl is obtained. Yield: 5.7 ta m
p227-231°C Reference Example 2 In the same manner as in Reference Example 1, 5-(p-toluenesulfonyloxy)-13,4-dihydrocarbostyryl is obtained.

mP 215-21600 Reference Example 3 4.5 ml of 5-methanesulfonyloxy-3,4-dihydrocarbostyryl was suspended in 90 m' of dioxane, and N
After adding 435 ml of aB, 5.3 ml of acetic acid is added dropwise.

After the dropwise addition, the mixture was heated under reflux for 1 hour, and then the solvent was distilled off under reduced pressure. Saturated sodium bicarbonate solution is added to the remaining bamboo, the precipitate is filtered and washed with chloroform, and the furnace solution is extracted with chloroform. After drying the chloroform layer with Na2S04, the solvent was distilled off, and the residue was purified using silica gel column chromatography [silica gel; Wako C-200 (manufactured by Wako Pure Chemical Industries, Ltd.], lacquer extract: chloroform), and then crystallized with petroleum ether. become The obtained crystals were recrystallized from methanol to form colorless prismatic crystals.
-methanesulfonyloxy-1'2'3,4-tetrahydroquinoline is obtained. yield. Reference Example 4 In the same manner as in Reference Example 3, 5-(p-toluenesulfonyloxy)-1,2,3,4-tetrahydroquinoline was obtained.

mPI12-11yo Reference Example 5 Add 21.6 mm of ethyl ethoxymethylene malonate to 22.4 mm of 5-methanesulfonyloxy-1,2,3,4-tetrahydroquinoline and heat for 30 minutes at 110 qo over a rope drop oil bath. .

Ethanol ooze is observed. After heating, 240 g of polyphosphoric acid prepared from 120 g of phosphoric acid and 120 g of phosphorus pentoxide was added, and the mixture was reacted for 45 minutes on a 14,000 liter oil tank. After the reaction, the mixture was cooled to room temperature, poured into 400 mL of water, cooled again on ice, and neutralized with a 40% aqueous solution of caustic soda to precipitate crystals. Add 150 μl of a 10% caustic soda aqueous solution to the obtained crystals and reflux for 4 minutes. After hot activated carbon treatment, treat in a furnace.
After cooling the furnace liquid and adjusting the pH to 2 with concentrated hydrochloric acid, the precipitated crystals were collected from the furnace. The fine crystals are recrystallized from dimethylformamide to obtain white needle-like crystals of 8-methanesulfonyloxy-6,7-dihydro-1-oxy-IH,QH-benzo[ij]quinolidine-2-carboxylic acid. Yield: 21.3 mp
270-275 051 (p-toluenesulfonyloxy)-1,2,3,4-tetrahydroquinoline 30.0
In the evening, 21.6 g of ethyl ethoxymethylene malonate was added, and the mixture was heated at 110°C for 3 minutes.

After heating, add 240 ml of polyphosphoric acid (prepared from 120 ml of phosphoric acid and 120 ml of phosphorus pentoxide) and heat on an oil bath at 1,400 C.
Let it react for 0 minutes. After the reaction, the mixture is cooled to room temperature, poured into the ground with 400 g of water, neutralized with a 40% aqueous solution of caustic soda, and the precipitated crystals are collected in a furnace. Add 150 ml of a 10% aqueous solution of caustic soda to the obtained crystals and reflux for 40 minutes. After hot activated carbon treatment, it is filtered through a furnace. After cooling the furnace liquid and adjusting the pH to 2 with concentrated hydrochloric acid, the precipitated crystals were collected from the furnace. The crude crystals were recrystallized from dimethylformamide to give white needle-like crystals of 8-(p-toluenesulfonyloxy)-6,7-dihydro-1-oxy-IH.
, 9H-penzo[ij]quinolidine-2-carboxylic acid is obtained. Yield 27.4 ta mp 30030 or more Reference example 7 8-chloro-6,7-dihydro-1-oxy-IH,9
H-penzo[ij]quinolidiso-2-carboxylic acid 19.
2 parts and 35.5 parts of Piverazine were added to 350 parts of anhydrous dimethyl sulfoxide and heated at 170-180 qo for 6 hours.

After the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was mixed with 5 ml of water.
After adding 0.00%, the pH is adjusted to 2 with concentrated hydrochloric acid, the insoluble matter is removed in the oven, the furnace solution is concentrated to about 100% under reduced pressure, and the pH is adjusted to 9 with 10% aqueous sodium hydroxide solution. Extract the alkaline aqueous solution with chloroform and extract. After removing the form-soluble substances, the alkaline aqueous layer is left and the precipitated crystals are collected in a furnace. Dissolve the obtained crude crystals on top of 10% aqueous sodium hydroxide solution! ．． , after activated carbon treatment, ``10%
Adjust the pH to 8 with an aqueous hydrochloric acid solution. The precipitated crystals are collected in a furnace,
After thorough washing with water, it is recrystallized from dimethylformamide to obtain white needle-like crystals of 81-(1-piverazinyl)-6,7-dihydro-1-oxo-IH, 9-benzo[ii]quinolidine-2-carboxylic acid. Yield 6.5ta mp2
67-268q○ Obtained 8-(1-piverazinyl)-
6,7-dihydro-1-oxo IH,9H-penzo
[ij] Quinolidine-2-carboxylic acid 6.4 water 50
After adding 15% 10% aqueous hydrochloric acid solution and removing insoluble matter in an oven, the sewage water was removed under reduced pressure to obtain white amorphous crystals.
-(1-piverazinyl)-6,7-dihydro-1-oxo IH,SH-penzo[ij]quinolidine-2-carboxylic hydrochloride is obtained.

Yield: 5.7 mp 30,000 or more Compounds shown in Table 2 were obtained in the same manner as in Reference Example 7 using appropriate starting materials.

Table 2 Reference Example 11 8-(p-Toluenesulfonyloxy)-6,7-dihydro-1-oxo-IH, 9 days-Benzo[ij]quinolidine-2-carboxylic acid 19.1 days and Piverazine 12.
The mixture was added to 200 M of anhydrous dimethyl sulfoxide and heated in an autoclave at 1 bar pressure of 150 to 160 oo for 1 hour under a nitrogen stream.

After the reaction is completed, the solvent and excess piverazine are removed under reduced pressure, methanol-ether is added to the residue, and the precipitate is filtered out and washed with ether. Pour the obtained crystals into 200 ml of water.
40% of a 10% aqueous hydrochloric acid solution was added and suspended, the insoluble matter was removed in a furnace, the furnace solution was neutralized with saturated sodium bicarbonate water, and this solution was mixed with Amberlite LH-20 (manufactured by Tokyo Organic Chemical Industry Co., Ltd.). After isolation and purification by packed column chromatography (eluate, water, ethanol), recrystallization from dimethylformamide gave white needle-like crystals of 8-(1-piverazinyl)-6,7-
Dihydro-1-oxo-IH,9H-penzo[ij]quinolidine-2-carboxylic acid is obtained. Yield: 2.7 mp
267-26 are ○ Example 1 8-(4-formyl-1-piverazinyl)-6,7-dihydro-1-oxo IH, 9 days-benzo[ij]quinolidine-2-carboxylic acid 0.85 days, dried dimethylformamide 25 days Suspended in triethylamine 0.42
Add the wings and chill on ice for 15 minutes.

Next, add 0.4' of isobutyl chlorocarbonate and cook at the same temperature.
Continue playing Takahiro for 8 minutes. Separately, 1.3 μm of ampicillin was suspended in 15% of dry dimethylformamide, 0.7 μl of triethylamine and 0.5 μm of anhydrous magnesium sulfate were added under ice cooling, and the insoluble matter was removed in an oven at the same temperature for 30 minutes. The triethylamine salt solution of ampicillin obtained was added to the above reaction mixture and allowed to stand for 2 hours under ice cooling. After the reaction, the insoluble matter is removed by furnace,
Add 2.5 parts of a 20% sodium 2-ethylhexanoate solution in n-butanol to the solution, and add 20% of ethyl ether.
The crystals precipitated by adding 100 ml of water are collected by furnace. Add this crystal to 1 liter of water.
00 on a desk, acidified with dilute hydrochloric acid to obtain a precipitated solid, washed with water, and dried at room temperature to obtain the desired 6-{2-[8
-(4-formyl-1-piverazinyl)-6,7-dihydro-1-oxo IH, 9 days-benzo[jj]quinolidine-2-carboxamide]-2-phenylacetamide}-3,3,-dimethyl-7-oxo-4-thia 1
-Azabicyclo[3,2,0]hebutane-2-carboxylic acid 0.87% is obtained. White amorphous crystal, mP217-2
24oo (decomposition) Example 2 8-(4-formyl-1-piverazinyl)6-1,7-dihydro-1-oxo-IH, 9 days-benzo[ij]quinolidine-2-carboxylic acid (0.85%) was suspended in dry dimethylformamide 25%, triethylamine Add 0.42' of water and cool on ice for 15 minutes.

Next, add 0.4 Z of isobutyl chlorocarbonate and add 4
Continue with Konagoma Tou Azusa. On the other hand, 1.3 mol of amoxicillin was suspended in 15 ml of dry dimethylformamide, and then mixed with 0.7 M of triethylamine and 0.5 ml of anhydrous magnesium sulfate.
After heating at the same temperature for 30 minutes, the triethylamine salt solution of amoxicillin obtained by removing the waste in the oven was added to the above reaction solution, and the solution was incubated under ice for 2 hours, followed by the same procedure as in Example 1. 6-{2-[8-1 (4-formyl-1
-piverazinyl)-6,7-dihydro-1-oxo-I
H, penzo[ij]quinolidine-2-carboxamide]-2-(4-hydroxy)phenylacetamide}
-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0]hebutane-2-carboxylic acid 1.
Get 0 nights. White amorphous crystal mp249-254oo (
Decomposition) Example 3 8-(1-pivedinyl)-6,7-dihydro-1-oxo IH,9H-penzo [ij]quinolidine-2-
Dry 0.78% carboxylic acid and 25% dimethylformamide
Add 0.42% of triethylamine, and stir under ice for 18 minutes.

Next, add 0.4 ml of isobutyl chlorocarbonate and cook at the same temperature.
Continue worshiping the lantern for a minute. Separately, 1.3 ml of ampicillin was suspended in 15 ml of dry dimethylformamide, 0.7 ml of triethylamine and 0.5 ml of anhydrous magnesium sulfate were added under ice, and the insoluble matter was removed in an oven after being soaked at the same temperature for 30 minutes. The obtained triethylamine salt solution of ampicillin was added to the above reaction solution and left to stand for 2 hours under ice cooling. After the reaction, the insoluble matter was removed in a furnace, and 2.5 cm of a 20% potassium 2-ethylhexanoate solution in n-butanol was added to the furnace solution, followed by 300 mg of ethyl ether to obtain the desired 61 {21]. 8-(1-piverazinyl)-6,7-dihydro-1-oxo-IH, 9-day-benzo [ij] quinolidine-2-ruboxamide]-121-phenylacetamide}-1-3,3-dimethyl-7-oxo-4-thia 1-azabicyclo 0.97 kg of [3,2,0]hebutane-2-carboxylic acid potassium salt is obtained. Pale yellow amorphous crystal, mp218-22500 (red change),
245-25 and 0 (Decomposition) Example 4 0.78 8-(1-piverazinyl)-6,7-dihydro-1-oxo IH,9H-penzo[ij]quinolidine-2-carboxylic acid was suspended in 25% of dry dimethylformamide, Add 0.42% of triethylamine and leave on ice for 15 minutes.

Next, add 0.4 ml of isobutyl chlorocarbonate and heat to 45 ml at the same temperature.
Continue stirring for a minute. Separately, 1.3 ml of amoxicillin was suspended in 15 ml of dry dimethylformamide, 0.7 ml of triethylamine and 0.5 ml of anhydrous magnesium sulfate were added under ice-cooling, and the mixture was stirred at the same temperature for 3 minutes, and the impurities were removed in an oven. The triethylamine salt solution of amoxicillin obtained in this manner was added to the above reaction mixture, and the mixture was cooled on ice for 2 hours. After the reaction, remove the impurities in the furnace,
Add 2.5 parts of a 20% sodium 2-ethylhexanoate solution in n-butanol to the furnace solution, and add 30 parts of ethyl ether.
Add zero heat and collect the precipitated crystals using a furnace. 1 ice in this crystal
A small amount of insoluble material is removed in an oven, and the solution is freeze-dried to obtain a white amorphous 6-{2-[8-(1-
piberazinyl)-6,7-dihydro-1-oxo-IH
, arc-benzo[ij]quinolidine-2-carboxamide]-2-(4-hydroxy)phenylacetamide}-
0.81 g of 3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0]hebutane-2-carboxylic acid sodium salt is obtained. White amorphous crystal elemental analysis value (
C33rd 36N606S・5. Calculated value (%) 53.25 6.32 11.29 Actual value (%) 52.97 6.12 11.08 Example 5
8-(4-acetyl-1-piverazinyl)-6,7-dihydro-1-oxo-IH, 9 days - 0.7 hours of benzo[ij]quinolidine-2-carboxylic acid was suspended over 20 minutes of dry dimethylformamide, and 0.7 hours of triethylamine was suspended over 20 minutes of dry dimethylformamide. Add 34 minutes of water and leave to cool on ice for 15 minutes.

Next, add 0.32% of isobutyl chlorocarbonate and stir at the same temperature for 45 minutes. Separately, 1 hour of ampicillin was suspended in 10'' of dry dimethylformamide, 0.5 hours of triethylamine and 0.4 hours of anhydrous magnesium sulfate were added under ice-cooling, and at the same temperature, the remaining particles were removed from the 3 ships. The triethylamine salt solution of ampicillin obtained by evaporation was added to the above reaction mixture and incubated under ice for 2 hours, and then treated in the same manner as in Example 1 to obtain the desired 61{21[81( 4-acetyl-1-piverazinyl)-6,7-dihydro-1-oxo-IH,Q
H-benzo[ij]quinolidine-2-carboxamide)
-21-phenylacetamide}-3,3-dimethyl-7
-Oxo-4-thia-1-azabicyclo[3,2,0]
0.75 kg of hebutane-2-carboxylic acid is obtained. White amorphous crystal mp214-21900 (decomposition) Example 68
-(4-methanesulfonyl-1-piverazinyl) -6,
7-dihydro 1-oxo-IH, 9 days-benzo [ij
] 0.81 g of quinolidine-2-carboxylic acid was suspended in 25 g of dry dimethylformamide, and 0.81 g of quinolidine-2-carboxylic acid was suspended in 25 g of dry dimethylformamide.
．． Add 42' and let it fly under the ice for 18 minutes.

Next is Ku. Add 0.4' of isobutyl carbonate at the same temperature.
Pray for 5 minutes. Separately, 1.3 ml of ampicillin was suspended in 15 ml of dry dimethylformamide, 0.7 ml of triethylamine and 0.5 ml of anhydrous magnesium sulfate were added under ice, and the solids were heated in a furnace at the same temperature for 30 minutes. The triethylamine salt solution of ampicillin obtained by removing the ampicillin was added to the above reaction mixture, and after cooling on ice for 2 hours, the solution was treated in the same manner as in Example 1 to obtain the desired white amorphous 6-{2-[ 8-(4-methanesulfonyl-1-piverazinyl)-6,7-dihydro-1-oxo IH, 9 days-benzo[ij]quinolidine-2-carboxamide]-2-phenylacetamide}-
3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0]hebutane-2-carboxylic acid 1.2
Get 5 evenings. mP182-1870 (degradation) Formulation Example 1 Dissolve the compound of the present invention and glucose in distilled water for injection, inject into an ampoule in step 5, and purify with nitrogen at 12 ro.
Autoclaving is performed for 5 minutes to obtain an injection having the above composition.

Formulation Example 2 Magnesium stearate is mixed, polished, and then compressed into tablets using a sugar coater with a RI ratio.

The obtained tablets were mixed with TC-5 and polyethylene glycol-6.
000, coated with a film coating agent consisting of castor oil and methanol to produce film-coated tablets of the above-mentioned composition. Formulation Example 3 Compound B 2 days purified lanolin 5 days white beeswax 5 days white petrolatum 88 days Total amount 100 days white beeswax was poured over to make a liquid, then the compound of the present invention, purified lanolin and white petrolatum were added and boiled until it became a liquid. After heating, the mixture is concentrated until it begins to solidify to obtain an ointment having the above composition.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 represents a hydrogen atom, a lower alkanoyl group, or a lower alkanesulfonyl group, and R^2 represents a hydrogen atom or a hydroxyl group, respectively. . ] Penicillanic acid derivatives and salts thereof.